WO2022166938A1 - 一种含羧酸酯片段的尿嘧啶类化合物、其制备方法、除草组合物和用途 - Google Patents

一种含羧酸酯片段的尿嘧啶类化合物、其制备方法、除草组合物和用途 Download PDF

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WO2022166938A1
WO2022166938A1 PCT/CN2022/075322 CN2022075322W WO2022166938A1 WO 2022166938 A1 WO2022166938 A1 WO 2022166938A1 CN 2022075322 W CN2022075322 W CN 2022075322W WO 2022166938 A1 WO2022166938 A1 WO 2022166938A1
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alkyl
compound
reaction
preparation
added
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PCT/CN2022/075322
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English (en)
French (fr)
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张璞
姚凯诚
吴耀军
徐丹
钱平
卜龙
白从强
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江苏中旗科技股份有限公司
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Priority to MX2023008736A priority Critical patent/MX2023008736A/es
Priority to JP2023547574A priority patent/JP2024507475A/ja
Priority to US18/276,036 priority patent/US11958813B2/en
Priority to CN202280002679.0A priority patent/CN115151531B/zh
Priority to EP22749217.0A priority patent/EP4289824A4/en
Priority to CA3199030A priority patent/CA3199030A1/en
Priority to KR1020237018516A priority patent/KR20230110530A/ko
Priority to AU2022215754A priority patent/AU2022215754B2/en
Publication of WO2022166938A1 publication Critical patent/WO2022166938A1/zh
Priority to ZA2023/05750A priority patent/ZA202305750B/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/54—1,3-Diazines; Hydrogenated 1,3-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P13/00—Herbicides; Algicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of pesticides and herbicides, in particular to a carboxylate fragment-containing uracil compound, its preparation method, herbicidal composition and use.
  • Chemical herbicides are the most economical and effective means of weed control. However, the long-term continuous high-dose use of a single species or single mode of action of chemical herbicides is likely to cause problems such as weed resistance and resistance evolution, and the development of new varieties of pesticides is the core method to solve the above problems.
  • Protoporphyrinogen oxidase catalyzes the oxidation of protoporphyrinogen IX to protoporphyrin IX, a key enzyme in the same biosynthetic step of chlorophyll and heme. Inhibition of PPO in plants will eventually lead to the accumulation and leakage of the substrate protoporphyrin IX into the cytoplasm, resulting in cytoplasmic lipid peroxidation and plant albino death. Over the past few decades, PPO has been extensively studied as an important herbicide target.
  • the technical problem to be solved by the present invention is to provide a novel uracil herbicide with good herbicidal activity.
  • a uracil compound containing a carboxylate fragment the structure of which is shown in the general formula (I):
  • R 1 and R 2 are respectively selected from hydrogen or methyl; or R 1 and R 2 together with the attached carbon form a three-membered ring;
  • R 3 is selected from C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkoxy C 1-3 alkyl, C 2-6 alkenyloxy C 1-3 alkyl, C 2-6 haloalkene Oxygen C 1-3 alkyl, C 2-6 alkynyloxy C 1-3 alkyl, C 2-6 haloalkynyloxy C 1-3 alkyl, C 1-3 alkane S(O) n C 1-3 Alkyl, C 3-6 epoxy alkyl, C 1-3 alkyl or C 3-9 epoxy alkyl;
  • n 0, 1 or 2;
  • R 1 is selected from hydrogen and R 2 is selected from methyl
  • the carbon atom attached to it can be selected from R type or S type, or a mixture of the two.
  • R 1 and R 2 are respectively selected from hydrogen or methyl; or R 1 and R 2 together with the attached carbon form a three-membered ring;
  • R 3 is selected from C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkoxy C 1-3 alkyl, C 2-6 alkenyloxy C 1-3 alkyl, C 2-6 haloalkene Oxy C 1-3 alkyl, C 2-6 alkynyloxy C 1-3 alkyl, C 2-6 haloalkynyloxy C 1-3 alkyl, C 3-6 epoxy alkyl C 1-3 alkyl or C 3-9 epoxy alkyl;
  • R 1 is selected from hydrogen and R 2 is selected from methyl group
  • the carbon atom connected to it can be selected from R type or S type, or a mixture of the two. In the mixture, the ratio of R to S is 1:99 to 99 :1.
  • R 1 and R 2 are respectively selected from hydrogen or methyl
  • R 3 is selected from C 1-3 alkoxy C 1-3 alkyl, C 1-3 haloalkoxy C 1-3 alkyl, C 2-6 alkenyloxy C 1-3 alkyl, C 2-6 haloalkene Oxy C 1-3 alkyl, C 2-6 alkynyloxy C 1-3 alkyl, C 2-6 haloalkynyloxy C 1-3 alkyl, C 3-6 epoxy alkyl C 1-3 alkyl or C 3-9 epoxy alkyl;
  • R 1 is selected from hydrogen and R 2 is selected from methyl group
  • the carbon atom connected to it can be selected from R type or S type, or a mixture of the two. In the mixture, the ratio of R to S is 1:99 to 99 :1.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Alkyl straight or branched chain alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl or sec-butyl and isomers.
  • Alkenyl Linear or branched alkenes such as vinyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl.
  • Alkynyl straight or branched chain alkynes such as ethynyl, propynyl and the different butynyl, pentynyl and hexynyl isomers. Alkynyl also includes polyalkynes such as 2,4-hexadiynyl.
  • Alkoxyalkyl alkyl-O - alkyl-, eg CH3OCH2- .
  • Haloalkoxyalkyl alkyl-O-alkyl-, the hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms, eg ClCH2OCH2- .
  • Alkynoxyalkyl Alkynyl - O - alkyl-, eg CH ⁇ CCH2OCH2CH2- , where O is not directly attached to CH ⁇ C.
  • Haloalkynyloxyalkyl alkynyl-O - alkyl-, the hydrogen atom on these alkynyl groups may be replaced by a halogen atom, eg ClC ⁇ CCH2OCH2CH2- .
  • Epoxyalkyl A substituted or unsubstituted cyclic oxyalkyl group, such as glycidyl.
  • Epoxyalkylalkyl A substituted or unsubstituted alkyl group bearing a cyclic oxyalkyl group, such as epoxybutyl, substituents such as methyl, halogen, cyano, and the like.
  • a second aspect of the present invention provides a method for synthesizing the above-mentioned carboxylate fragment-containing uracil compound, the specific method comprising: in the presence of a solvent, mixing the acid compound represented by formula (II) with a different A substituted alcohol, halogenated or sulfonic acid ester compound is subjected to a contact reaction,
  • the above reaction temperature is 0-160°C, preferably 20-120°C; the time is 2-15h, preferably 3-12h.
  • the above reaction solvent is selected from methylene chloride, 1,2-dichloroethane, tetrahydrofuran, acetonitrile, 1,4-dioxane, toluene, o-xylene, m-xylene, p-xylene, n-heptane, n- At least one of octane and n-nonane.
  • the molar ratio of the carboxylic acid compound represented by formula (II) to the different substituted alcohol, halogenated or sulfonic acid ester compound is 1:1-4; preferably 1:1.1-3.
  • Partial compounds of general formula (I) of the present invention can be directly obtained by further esterification of intermediates 1-8;
  • Partial compounds of general formula (I) of the present invention can also be directly esterified with intermediates 1-8 to obtain carboxylic acids of general formula (II), or hydrolyzed corresponding esters to obtain carboxylic acids of general formula (II).
  • the carboxylic acid of the general formula (II) can be further prepared into the corresponding acid chloride, and then contacted and reacted with different substituted alcohols to obtain the partial compound of the general formula (I) of the present invention; the carboxylic acid of the general formula (II) can also be obtained by The dehydrating agent and different substituted alcohols can be contacted and reacted to obtain the general formula (I) of the present invention; Partial compounds of formula (I).
  • the reaction is carried out in a suitable solvent, which can be selected from benzene, toluene, xylene, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, chloroform, 1 , 2-dichloroethane or ethyl acetate.
  • a suitable solvent which can be selected from benzene, toluene, xylene, acetone, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, chloroform, 1 , 2-dichloroethane or ethyl acetate.
  • the alkali can be selected from alkali metal hydrides, such as sodium hydride, lithium hydride or sodium amide, etc.; alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide; alkali metal carbonates, such as sodium carbonate or potassium carbonate ; Organic bases, such as pyridine, 4-dimethylaminopyridine, triethylamine, N-methylpyrrole or diisopropylethylamine, etc.; in the case of using a dehydrating agent, as a dehydrating agent that can be used, such as 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, N,N-dicyclohexylcarbodiimide, etc.; acylating reagents, such as bis(chloride) chloride, can be used to prepare acid chlorides sulfone, oxalyl chloride, etc.
  • the reaction temperature can be between -10°C and the
  • R 3 -X or R 3 -OH are commercially available.
  • X is a leaving group, X is selected from chlorine, bromine, iodine or sulfonate.
  • the aforementioned method of the present invention may also include necessary pre-treatment of the aforementioned raw materials and necessary post-treatment operations on the reaction product.
  • the operation means of pre-treatment and post-treatment include but are not limited to drying, washing, beating, filtration, centrifugation, Column chromatography, recrystallization, etc.
  • the example section of the present invention provides several specific processing means, which should not be construed as a limitation of the present invention by those skilled in the art.
  • the third aspect of the present invention provides the use of a carboxylate moiety-containing uracil compound as a herbicide.
  • the fourth aspect of the present invention provides a herbicidal composition, which uses the compound of general formula (I) as an active component, and the weight percentage of the active component in the composition is 0.1-99.9%.
  • the compounds of the present invention have excellent killing activity against a broad spectrum of economically important monocotyledonous and dicotyledonous annual harmful plants, can effectively control a variety of weeds, can obtain good effects at low doses, can be used as herbicide.
  • the present invention therefore also includes the use of compounds of general formula (I) for controlling weeds.
  • the present invention relates to a method for controlling unwanted plants or for regulating the growth of plants, wherein one or more compounds according to the invention are applied to plants (eg harmful plants such as monocotyledonous or dicotyledonous weeds or unwanted plants) crop plants), seeds (eg grains, seeds or vegetative propagules such as tubers or shoots with buds) or plant growth areas (eg cultivation areas).
  • plants eg harmful plants such as monocotyledonous or dicotyledonous weeds or unwanted plants
  • seeds eg grains, seeds or vegetative propagules such as tubers or shoots with buds
  • plant growth areas eg cultivation areas.
  • the compounds of the invention can be applied before planting (and if appropriate also by introduction into the soil), pre-emergence or post-emergence.
  • the following examples of various representative monocotyledonous and dicotyledonous weed flora controlled by the compounds of the present invention are mentioned only to illustrate the present invention, but in no way limit it.
  • Monocotyledonous harmful plant genera Aegilops, Agropyron, Agrostis, Alopecurus, Apera, Avena, Brachiaria , Bromus, Cenchrus, Commelina, Cynodon, Cyperus, Dactyloctenium, Digitaria ), Echinochloa, Eleocharis, Eleusine, Eragrostis, Eriochloa, Festuca, Fimbristylis, Heteranthera, Imperata, Ischaemum, Leptochloa, Lolium, Monochoria, Panicum, Sparrow Paspalum, Phalaris, Phleum, Poa, Rottboellia, Sagittaria, Scirpus, Setaria (Setaria), Sorghum (Sorghum).
  • Dicotyledonous weeds Abutilon, Amaranthus, Ambrosia, Anoda, Anthemis, Aphanes, Artemisia, Atriplex, Bellis, Bidens, Capsella, Carduus, Cassia, Centaurea, Chenopodium, Thistle Cirsium), Convolvulus, Datura, Desmodium, Emex, Erysimum, Euphorbia, Weasel Genus Galeopsis, Galinsoga, Galium, Hibiscus, Ipomoea, Kochia, Lamium, Solitary (Lepidium), Lindernia, Matricaria, Mentha, Mercurialis, Mullugo, Myosotis, Papaver, Morning glory Pharbitis, Plantago, Polygonum, Portulaca, Ranunculus, Raphanus, Rorippa, Rotala , Rumex, Salsola, Senecio, Sesbania, Sida, Sinapis, Solanum, bitter Sonchu
  • the growth of the harmful plant seeds stops after the treatment, and the harmful plants stay in the growth phase at the application time point, or die completely after a certain period of time, so that it can be Time points eliminate competition from weeds that are detrimental to crop plants in a durable manner.
  • the compounds of the present invention When the compounds of the present invention are applied to green plant parts after emergence, the growth stops after the treatment, and the harmful plants stay in the growth phase at the time of application, or die completely after a certain period of time, so that very early time points can be achieved. Eliminates competition from weeds that are harmful to crop plants in a lasting way.
  • the technical solution of the present invention also includes the use of the compound of general formula (I) for controlling weeds.
  • the compounds of the general formula (I) according to the invention are also suitable for drying and/or defoliation of plants.
  • the present invention provides a pesticide herbicide, which is composed of an active ingredient and an auxiliary material, and the active ingredient includes at least one of the aforementioned carboxylate fragment-containing uracil compounds.
  • the content of the active ingredient in the pesticide herbicide is 0.1-99.9% by weight.
  • the present invention has no particular limitation on the specific types of adjuvants in the herbicide, for example, various surfactants and solvents commonly used in the field of herbicides can be used.
  • the carboxylate fragment-containing uracil compound of the present invention can be dissolved and diluted with a solvent for later use, and the concentration after dissolution and dilution with a solvent is preferably 0.05-0.4 g/L.
  • the solvent for dissolving the carboxylate fragment-containing uracil compound can include at least one of dimethyl sulfoxide and N,N-dimethylformamide, and the dilution reagent can be water containing common additives Wait.
  • additives commonly used in herbicides in the art such as one or more of surfactants, emulsifiers, etc., may also be added to the solution in which the uracil compound is dissolved.
  • the carboxylate fragment-containing uracil compound of the present invention can be used alone or in combination with other commonly used compounds.
  • the herbicides such as atrazine, tetrazolam, bromoxynil, cyclopentazone, mesotrione, etc.
  • the ratio of the compounded use is not particularly limited. The selection is made according to the ratio routinely used in the field, as long as the control effect after compounding can be enhanced, the scope of use can be enlarged and the safety can be improved.
  • the carboxylate fragment-containing uracil compound provided by the present invention has better herbicidal activity.
  • Example 163 was prepared using intermediate 156-3 and 2-(allyloxy)ethanol described in Example 23.
  • Example 17 compound 181 was prepared using intermediate 156-3 and a propynyl alcohol ethoxy compound described in Example 23.
  • Step 1 Preparation of compound 190
  • Example 22 compound 199 was prepared using intermediate 156-3 and (R)-glycidol described in Example 23.
  • Compound 302 was prepared by following the methods of Example 38, Example 39 using intermediate 258-3 and ( ⁇ )-glycidol described in Example 37.
  • the herbicidal activity test method of the compounds of the present invention is as follows:
  • Quantitative gramineous weeds (barnyardgrass, beef tendon grass, crabgrass, Japanese chinensis, serratia, chinensis, club head grass, kangaroo, multiflora ryegrass, bluegrass), broadleaf Seeds of leaf weeds (snake sausage, amaranth, wild rape, ox chickweed, small fly, sedge) and broken rice sedge were sown in 7 cm diameter with holes in nutrient soil (sand soil, pH 6 .1, organic matter 1%) in a plastic pot, cover the soil with appropriate amount of soil after sowing, and then soak the soil by absorbing water at the bottom, place it in a constant temperature light cultivation room for 24 hours and then carry out soil spraying.
  • nutrient soil sand soil, pH 6 .1, organic matter 16%
  • the spraying adopts the Nanjing Agricultural Mechanization Research Institute of the Ministry of Agriculture.
  • the 3WP-2000 walking spray tower produced the spindle speed is 96mm/r, the spray height is 300mm, the effective spray width of the nozzle is 350mm, the spray area is 0.35m 2 , and the nozzle flow rate is 390mL/min;
  • A indicates that the inhibition rate is greater than or equal to 85% to 100%
  • C means the inhibition rate is greater than or equal to 55% to less than 70%
  • D indicates that the inhibition rate is less than 55%.
  • test results show that the compound of general formula (I) generally has an excellent control effect on a variety of weeds at a dose of 30 g ai/hm 2 , reaching the control effect of class A.
  • Table 2 Herbicidal activities of some compounds of general formula I and control compounds (post-emergence, fresh weight inhibition rate %)

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Abstract

本发明涉及农药除草剂领域，具体涉及一种含羧酸酯片段的尿嘧啶类化合物、其制备方法、除草组合物和用途。本发明提供的含羧酸酯片段的尿嘧啶类化合物相比现有技术，具有更好的除草活性。

Description

[根据细则26改正07.05.2022]　一种含羧酸酯片段的尿嘧啶类化合物、其制备方法、除草组合物和用途 技术领域
本发明涉及农药除草剂领域，具体涉及一种含羧酸酯片段的尿嘧啶类化合物、其制备方法、除草组合物和用途。
背景技术
采用除草剂化学除草是杂草防除中最为经济、有效的手段。但长期连续高剂量地使用单一品种或单一作用方式的化学除草剂，容易造成杂草耐药和抗性演化等问题，而开发新型品种农药是解决上述问题的核心手段。
原卟啉原氧化酶(PPO，EC 1.3.3.4)能够将原卟啉原IX催化氧化成原卟啉IX，其是叶绿素和亚铁血红素相同生物合成步骤中的一个关键酶。抑制植物体内的PPO，将会最终导致底物原卟啉IX的积累并泄漏到细胞质中，从而引起细胞质脂质过氧化及植株白化死亡。在过去的几十年中，PPO作为一个重要的除草剂靶标已得到了广泛研究。
其中尿嘧啶类化合物作为除草剂的研究始于20世纪60年代，在90年代达到高峰，近年来开发品种数量不多，但也时有专利报道，如CIBA-GEIGY公司在US5183492A中公开了如下通式的结构：
Figure PCTCN2022075322-appb-000001
后由先正达公司成功开发出了商品化除草剂Butafenacil(US5183492A中的化合物47)，主要用于果园，包括葡萄园、棉花地、非耕地防除重要的禾本科杂草、阔叶杂草、莎草等，具有良好的除草效果。
Figure PCTCN2022075322-appb-000002
US5183492A同时公开了如下苯甲酸基丙酸酯CK(申请书中的化合物1)的制备：
Figure PCTCN2022075322-appb-000003
总而言之，现有的尿嘧啶类化合物除草剂种类较为单一，选择余地较小，市场上仍然迫切需要具有良好的除草活性的新型尿嘧啶类除草剂。
发明内容
本发明要解决的技术问题是：提供一种具有良好的除草活性的新型尿嘧啶类除草剂。
本发明解决上述技术问题的技术方案如下：
一种含羧酸酯片段的尿嘧啶类化合物，其结构如通式(I)所示：
Figure PCTCN2022075322-appb-000004
式中：
R 1、R 2分别选自氢或甲基；或者R 1和R 2与所连接的碳一起形成三元环；
R 3选自C 1～3烷氧C 1～3烷基、C 1～3卤代烷氧C 1～3烷基、C 2～6烯氧C 1～3烷基、C 2～6卤代烯氧C 1～3烷基、C 2～6炔氧C 1～3烷基、C 2～6卤代炔氧C 1～3烷基、C 1～3烷S(O) nC 1～3烷基、C 3～6环氧烷基C 1～3烷基或C 3～9环氧烷基；
n＝0，1或2；
当R 1选自氢、R 2选自甲基时，与其相连的碳原子可选自R型或S型，或者为二者的混合物。
本发明较为优选的化合物为，通式(I)中：
R 1、R 2分别选自氢或甲基；或者R 1和R 2与所连接的碳一起形成三元环；
R 3选自C 1～3烷氧C 1～3烷基、C 1～3卤代烷氧C 1～3烷基、C 2～6烯氧C 1～3烷基、C 2～6卤代烯氧C 1～3烷基、C 2～6炔氧C 1～3烷基、C 2～6卤代炔氧C 1～3烷基、C 3～6环氧烷基C 1～3烷基或C 3～9环氧烷基；
当R 1选自氢、R 2选自甲基时，与其相连的碳原子可选自R型或S型，或者为二者的混合物，混合物中，R与S的比例为1：99至99：1。
本发明更为优选的化合物为，通式(I)中：
R 1、R 2分别选自氢或甲基；
R 3选自C 1～3烷氧C 1～3烷基、C 1～3卤代烷氧C 1～3烷基、C 2～6烯氧C 1～3烷基、C 2～6卤代烯氧C 1～3烷基、C 2～6炔氧C 1～3烷基、C 2～6卤代炔氧C 1～3烷基、C 3～6环氧烷基C 1～3烷基或C 3～9环氧烷基；
当R 1选自氢、R 2选自甲基时，与其相连的碳原子可选自R型或S型，或者为二者的混合物，混合物中，R与S的比例为1：99至99：1。
上面给出的通式(I)化合物的定义中，汇集所用术语一般定义如下：
卤素：指氟、氯、溴或碘。烷基：直链或支链烷基，例如甲基、乙基、丙基、异丙基、正丁基、叔丁基或仲丁基及异构体。烯基：直链或支链烯类，例如乙烯基、1-丙烯基、2-丙烯基和不同的丁烯基、戊烯基和己烯基异构体。烯基还包括多烯类，如1,2-丙二烯基和2,4-己二烯基。炔基：直链或支链炔类，例如乙炔基、丙炔基和不同的丁炔基、戊炔基和己炔基异构体。炔基还包括多炔类，如2,4-己二炔基。烷氧基烷基：烷基-O-烷基-，如CH 3OCH 2-。卤代烷氧烷基：烷基-O-烷基-，在这些烷基上的氢原子可部分或全部被卤原子所取代，例如ClCH 2OCH 2-。烯氧烷基：烯基-O-烷基-，例如CH 2＝CHCH 2OCH 2CH 2-。卤代烯氧烷基：烯基-O-烷基-，其中O与CH 2＝CH并不直接相连，在这些烯基上的氢原子可部分或全部被卤原子所取代，例如ClCH＝CHCH 2OCH 2CH 2-。炔氧烷基：炔基-O-烷基-，例如CH≡CCH 2OCH 2CH 2-，其中O与CH≡C并不直接相连。卤代炔氧烷基：炔基-O-烷基-，在这些炔基上的氢原子可被卤原子所取代，例如ClC≡CCH 2OCH 2CH 2-。烷S(O) n烷基：烷基-S(O) n-烷基-，n＝0，1或2，如CH 3SCH 2CH 2-、CH 3SOCH 2CH 2-、CH 3SO 2CH 2CH 2-。环氧烷基：取代或未取代的环状含氧烷基，例如环氧丙基。取代基如甲基、卤素、氰基等。环氧烷基烷基：取代或未取代的带有环状含氧烷基的烷基，例如环氧丁基，取代基如甲基、卤素、氰基等。
本发明的部分化合物可以用表1中列出的具体化合物来说明，但本发明并不仅限于这些化合物。
Figure PCTCN2022075322-appb-000005
表1
Figure PCTCN2022075322-appb-000006
Figure PCTCN2022075322-appb-000007
Figure PCTCN2022075322-appb-000008
Figure PCTCN2022075322-appb-000009
Figure PCTCN2022075322-appb-000010
Figure PCTCN2022075322-appb-000011
Figure PCTCN2022075322-appb-000012
Figure PCTCN2022075322-appb-000013
Figure PCTCN2022075322-appb-000014
Figure PCTCN2022075322-appb-000015
Figure PCTCN2022075322-appb-000016
Figure PCTCN2022075322-appb-000017
Figure PCTCN2022075322-appb-000018
Figure PCTCN2022075322-appb-000019
Figure PCTCN2022075322-appb-000020
Figure PCTCN2022075322-appb-000021
Figure PCTCN2022075322-appb-000022
Figure PCTCN2022075322-appb-000023
本发明的第二方面提供了上述含羧酸酯片段的尿嘧啶类化合物的合成方法，具体的该方法包括：在溶剂存在的条件下，将式(II)所示的酸类化合物与不同的取代的醇、卤代或磺酸酯化合物进行接触反应，
Figure PCTCN2022075322-appb-000024
其中，在通式(I)和(II)，所涉及的R 1、R 2和R 3的定义均与权利要求1中的定义相同。
上述反应温度为0～160℃，优选为20～120℃；时间为2～15h，优选为3～12h。
上述反应溶剂选自二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、1,4-二氧六环、甲苯、邻二甲苯、间二甲苯、对二甲苯、正庚烷、正辛烷和正壬烷中的至少一种。
上述反应中，式(II)所示的羧酸类化合物与不同的取代的醇、卤代或磺酸酯化合物用量摩尔比为1：1～4；优选为1：1.1～3。
本发明的通式(I)部分化合物可通过中间体1-8进一步酯化直接得到；
Figure PCTCN2022075322-appb-000025
本发明的通式(I)部分化合物也可由中间体1-8酯化直接得通式(II)羧酸，或通过水解相应的酯得到通式(II)羧酸。通式(II)羧酸可以进一步被制备成相应的酰基氯后，与不同的取代的醇进行接触反应的得到本发明的通式(I)部分化合物；通式(II)羧酸也可以通过脱水剂与不同的取代的醇进行接触反应的得到本发明的 通式(I)部分化合物通式；(II)羧酸还可以与卤代或磺酸酯化合物进行接触反应的得到本发明的通式(I)部分化合物。
Figure PCTCN2022075322-appb-000026
反应在适宜的溶剂中进行，适宜的溶剂可选自苯、甲苯、二甲苯、丙酮、四氢呋喃、乙腈、N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二氯甲烷、氯仿、1,2-二氯乙烷或乙酸乙酯等。反应可以在有碱或无碱存在下进行，当在有碱存在下进行反应时，可加速反应进行。所述的碱可以选自碱金属氢化物，如氢化钠、氢化锂或氨基钠等；碱金属氢氧化物，如氢氧化钠或氢氧化钾；碱金属碳酸盐，如碳酸钠或碳酸钾；有机碱类，如吡啶、4-二甲氨基吡啶、三乙胺、N-甲基吡咯或二异丙基乙基胺等；在使用脱水剂的情况下，作为可使用的脱水剂，如1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、N,N-二环己基碳二亚胺等；制备酰基氯可使用酰化试剂，如氯化亚砜、草酰氯等。反应温度可在-10℃至反应中所选用的适宜的溶剂沸点温度之间，通常为0～100℃。反应时间为30分钟至20小时，通常1～10小时。
R 3-X或R 3-OH均有市售。X是离去基团，X选自氯、溴、碘或磺酸酯。
本发明的前述方法中还可以包括对前述原料进行必要的预处理和对反应产物进行必要的后处理操作，预处理和后处理的操作手段包括但不限于干燥、洗涤、打浆、过滤、离心、柱层析、重结晶等。本发明的实例部门提供了几种具体的处理手段，本领域技术人员不应理解为对本发明的限制。
除另有注明外，反应式中各基团定义同前。
本发明的第三方面提供了含羧酸酯片段的尿嘧啶类化合物在作为除草剂中的用途。
本发明的第四方面提供了一种除草组合物，其以通式(I)化合物作为活性组分，组合物中活性组分的重量百分含量为0.1-99.9％。
本发明的化合物对广谱的经济上重要的单子叶和双子叶一年生有害植物具有杰出的杀除活性，可以有效地控制多种杂草，在低剂量下就可以获得很好的效果，可用作除草剂。因此本发明还包括通式(I)化合物用于控制杂草的用途。
因此，本发明涉及一种防治不想要的植物或用于调节植物生长的方法，其中将一种或多种本发明化合物施用于植物(例如有害植物，如单子叶或双子叶杂草或不想要的作物植物)、种子(例如谷粒、种子或无性繁殖体，如块茎或带芽的幼枝部位)或植物生长区域(例如栽培区域)。本发明化合物可在种植前(如果合适，还通过引入土壤中)、苗前或苗后施用。下面所提及的本发明化合物防治的各种代表性的单子叶和双子叶杂草植物群例子仅用来说明本发明，但绝不限定本发明。
单子叶有害植物属：山羊草属(Aegilops)、冰草属(Agropyron)、剪股颖属Agrostis)、看麦娘属(Alopecurus)、Apera、燕麦属(Avena)、臂形草属(Brachiaria)、雀麦属(Bromus)、蒺藜草属(Cenchrus)、鸭跖草属(Commelina)、狗牙根属(Cynodon)、莎草属(Cyperus)、龙爪茅属(Dactyloctenium)、马唐属(Digitaria)、稗属(Echinochloa)、荸荠属(Eleocharis)、蟋蟀草属(Eleusine)、画眉草属(Eragrostis)、野黍属(Eriochloa)、羊 茅属(Festuca)、飘拂草属(Fimbristylis)、异蕊花属(Heteranthera)、白茅属(Imperata)、鸭嘴草属(Ischaemum)、千金子属(Leptochloa)、黑麦草属(Lolium)、雨久花属(Monochoria)、黍属(Panicum)、雀稗属(Paspalum)、虉草属(Phalaris)、梯牧草属(Phleum)、早熟禾属(Poa)、筒轴茅属(Rottboellia)、慈姑属(Sagittaria)、莞草属(Scirpus)、狗尾草属(Setaria)、高粱属(Sorghum)。
双子叶杂草属：白麻属(Abutilon)、苋属(Amaranthus)、豚草属(Ambrosia)、Anoda、春黄菊属(Anthemis)、Aphanes、蒿属(Artemisia)、滨藜属(Atriplex)、雏菊属(Bellis)、鬼针属(Bidens)、荠属(Capsella)、飞廉属(Carduus)、决明属(Cassia)、矢车菊属(Centaurea)、藜属(Chenopodium)、蓟属(Cirsium)、旋花属(Convolvulus)、曼陀罗属(Datura)、山蚂蝗属(Desmodium)、刺酸模属(Emex)、糖芥属(Erysimum)、大戟属(Euphorbia)、鼬瓣花属(Galeopsis)、牛膝菊属(Galinsoga)、拉拉藤属(Galium)、芙蓉属(Hibiscus)、番薯属(Ipomoea)、地肤属(Kochia)、野芝麻属(Lamium)、独行菜属(Lepidium)、母草属(Lindernia)、母菊属(Matricaria)、薄荷属(Mentha)、山靛属(Mercurialis)、Mullugo、勿忘我属(Myosotis)、罂粟属(Papaver)、牵牛属(Pharbitis)、车前属(Plantago)、蓼属(Polygonum)、马齿苋属(Portulaca)、毛茛属(Ranunculus)、萝卜属(Raphanus)、蔊菜属(Rorippa)、节节菜属(Rotala)、酸模属(Rumex)、猪毛菜属(Salsola)、千里光属(Senecio)、田菁属(Sesbania)、黄花稔属(Sida)、白芥属(Sinapis)、茄属(Solanum)、苦苣菜属(Sonchus)、尖瓣花属(Sphenoclea)、繁缕属(Stellaria)、蒲公英属(Taraxacum)、菥蓂属(Thlaspi)、车轴草属(Trifolium)、荨麻属(Urtica)、婆婆纳属(Veronica)、堇菜属(Viola)、苍耳属(Xanthium)。
当将本发明化合物在苗前施用于土壤中时，有害植物种子在处理后生长停止，有害植物停留在施用时间点时的生长期，或在一定时间段后彻底死亡，从而能够在极早的时间点以持久的方式消除对作物植物有害的杂草的竞争。
当将本发明化合物在苗后施用于绿色植物部位时，在处理后生长停止，有害植物停留在施用时间点时的生长期，或在一定时间段后彻底死亡，从而能够在极早的时间点以持久的方式消除对作物植物有害的杂草的竞争。
因此本发明的技术方案还包括通式(I)化合物用于控制杂草的用途。
此外，本发明通式(I)化合物也适用于植物的干燥和/或脱叶。
如前所述，本发明提供了一种农药除草剂，该农药除草剂由活性成分和辅料组成，所述活性成分包括前述的含羧酸酯片段的尿嘧啶类化合物中的至少一种。
优选情况下，所述活性成分在所述农药除草剂中的含量为0.1-99.9重量％。
本发明对所述除草剂中的辅料的具体种类没有特别的限制，例如可以为除草剂领域内常用的各种表面活性剂、溶剂等。
例如，本发明所述的含羧酸酯片段的尿嘧啶类化合物能够用溶剂溶解并稀释后备用，用溶剂溶解并稀释后的浓度优选为0.05-0.4g/L。溶解所述含羧酸酯片段的尿嘧啶类化合物的溶剂可以包括二甲亚砜、N,N-二甲基甲酰胺中的至少一种，所述稀释用的试剂可以为含有常用添加剂的水等。优选情况下，还可以向溶解有所述尿嘧啶类化合物的溶液中添加本领域内除草剂中常用的添加剂，如表面活性剂、乳化剂等中的一种或多种。
为了增强本发明所述的含羧酸酯片段的尿嘧啶类化合物的防治效果，增大其使用范围，本发明的含羧酸酯片段的尿嘧啶类化合物既可以单独使用，也可以与其它常用的除草剂(如莠去津、四唑酰草胺、溴苯腈、环戊恶草酮、硝磺草酮等)复配使用，而且对所述复配使用的比例没有特别的限定，可以根据本领域内常规使用的比例进行选择，只要复配后的防治效果能够增强，使用范围能够增大以及安全性能够得到提高即可。
本发明中化合物的中文命名与结构式有冲突的，以结构式为准；结构式有明显错误的除外。
本发明提供的含羧酸酯片段的尿嘧啶类化合物相比现有技术，具有更好的除草活性。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1：中间体1-8的制备
Step 1：中间体1-1的制备
Figure PCTCN2022075322-appb-000027
将20g的2-氯-4-氟苯甲酸、100g的乙醇放入500mL四口瓶中搅拌，降温至0℃，缓慢滴加17.73g的氯化亚砜，全程保持在0℃以下，待滴加完氯化亚砜后，升温至75℃回流搅拌，反应过夜，旋干反应液，得23.01g中间体1-1。
Step 2：中间体1-2的制备
Figure PCTCN2022075322-appb-000028
将67.46g中间体1-1、337.3g的1,2-二氯乙烷加入1L四口瓶，降温至0℃，缓慢滴加42.09g发烟硝酸(90％)和60.12g硫酸(98％)，滴毕，缓慢升至室温，搅拌至反应完成，将反应液转移至分液漏斗中，静至分层，取有机相，无机相用1,2-二氯乙烷萃取，有机相里的酸用冰水洗脱，直至水相pH值为7.0左右，旋干溶剂，得粗品89.81g。加入5倍质量的正己烷，重结晶，抽滤，干燥滤饼，得42.45g中间体1-2。
Step 3：中间体1-3的制备
Figure PCTCN2022075322-appb-000029
将60.84g中间体1-2，4.87g的Pt/C(5％)，300mL乙醇加入1L高压釜中，控制氢气压力2MPa，温度45℃反应11小时后，抽滤去除Pt/C后，旋干滤液，得中间体1-3粗品52.48g。
Step 4：中间体1-4的制备
Figure PCTCN2022075322-appb-000030
将52.48g中间体1-3的粗品、24.78g吡啶、262.4g的二氯甲烷加入500mL的四口瓶室温搅拌，5min后称取34.02g的氯甲酸乙酯用68.04g的二氯甲烷稀释后，缓慢滴加，1小时滴毕。反应5小时，调节pH值呈弱酸性，加入水，二氯甲烷萃取，旋干有机相，得中间体1-4粗品69.62g。
Step 5：中间体1-5的制备
Figure PCTCN2022075322-appb-000031
将12.98g的乙醇钠溶于38g的DMF中搅拌，冰浴降温至5℃。冰浴下滴加3-氨基-4,4,4-三氟丁烯酸乙酯(27.95g)的DMF(28g)溶液。滴毕然后滴加36.84g中间体1-4的DMF溶液，滴毕，升温至100℃下搅拌5h，反应完成后，调节pH至酸性，用乙酸乙酯萃取，饱和食盐水洗涤有机相，无水硫酸钠干燥、旋干溶剂，得粗品50g，柱层析纯化，得19.05g中间体1-5。
Step 6：中间体1-6的制备
Figure PCTCN2022075322-appb-000032
将19.05g中间体1-5，8.287g无水碳酸钾加入单口瓶，用60g的THF溶解，加入7.566g硫酸二甲酯，室温搅拌过夜。反应完成后，旋干THF，用乙酸乙酯萃取，无水硫酸钠干燥，旋干有机相，得中间体1-6粗品19.62g。
Step 7：中间体1-7的制备
Figure PCTCN2022075322-appb-000033
室温下将19.62g中间体1-6溶于150mL冰醋酸，加入同体积的36％的盐酸，回流反应8h。反应完成后，减压蒸除多余溶剂，向残余物中加入水，有固体析出，搅拌，抽滤，滤饼用水淋洗3次，60℃烘干，得中间体1-7粗品12.73g。
Step 8：中间体1-8的制备
Figure PCTCN2022075322-appb-000034
将6.8g中间体1-7、35g的1,2-二氯乙烷、1滴DMF、3.316g二氯亚砜加入100ml单口瓶，回流反应3h。反应完成后，旋干多余二氯亚砜和溶剂，得中间体1-8粗品6.22g。
实施例2：化合物3的制备
Step 1：中间体3-1的制备
Figure PCTCN2022075322-appb-000035
将实施例1中描述的中间体1-8(1g)，乙醇酸甲酯320mg加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加394mg三乙胺，滴毕后室温反应2h。反应完成后，柱层析纯化，得1.02g中间体3-1。
Step 2：中间体3-2的制备
Figure PCTCN2022075322-appb-000036
将1.02g中间体3-1，6.12g盐酸(36％)，6.12g醋酸加入反应瓶，回流40min，旋干反应液，得1.01g中间体3-2。
Step 3：中间体3-3的制备
Figure PCTCN2022075322-appb-000037
将1.01g中间体3-2、340mg二氯亚砜、2滴DMF、5.5g二氯乙烷加入反应瓶，回流反应3h，旋干反应液，得1.02g中间体3-3。
Step 4：化合物3的制备
Figure PCTCN2022075322-appb-000038
将103.29mg的乙二醇甲醚，228.95mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加上步制备的中间体3-3(0.50g)的3mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得165mg化合物3。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝7.8Hz,1H),7.95(d,J＝9.6Hz,1H),6.62(s,1H),4.99(s,2H),4.30–4.23(m,2H),3.59–3.52(m,2H),3.42(s,3H),3.26(s,3H).LCMS(ESI)[M+H] +＝483.05,Found＝482.61.
实施例3：化合物10的制备
Step 1：化合物10的制备
Figure PCTCN2022075322-appb-000039
将99.83mg的2-(烯丙氧基)乙醇，123.60mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例2中描述的中间体3-3(0.40g)的2.5mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得260mg淡黄色油状物为化合物10。 1H NMR(400MHz,DMSO-d6)δ8.16(d,J＝7.7Hz,1H),7.94(d,J＝9.6Hz,1H),6.61(s,1H),5.93–5.72(m,1H),5.24(dq,J＝17.4,1.8Hz,1H),5.13(dt,J＝10.1,1.6Hz,1H),4.99(s,2H),4.27(dd,J＝5.6,3.6Hz,2H),3.96(dt,J＝5.4,1.6Hz,2H),3.67–3.55(m,2H).LCMS(ESI)[M+H] +＝509.07,Found＝508.62.
实施例4：化合物28的制备
Step 1：化合物28的制备
Figure PCTCN2022075322-appb-000040
将95.70mg的2-(炔丙氧基)乙醇，148.82mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例2中描述的中间体3-3(0.50g)的3mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得110mg淡黄色油状物为化合物28。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝7.7Hz,1H),7.94(d,J＝9.6Hz,1H),6.61(s,1H),4.98(s,2H),4.27(dd,J＝5.7,3.4Hz,2H),4.16(d,J＝2.4Hz,2H),3.75–3.63(m,2H),3.43(d,J＝11.5Hz,4H).LCMS(ESI)[M+H] +＝507.05,Found＝506.83.
实施例5：中间体54-3的制备
Step 1：中间体54-1的制备
Figure PCTCN2022075322-appb-000041
将20g实施例1中描述的中间体1-8，4.86g的D-乳酸甲酯，100g二氯甲烷加入反应瓶中，氮气鼓吹，室温搅拌。60min内滴加5.9g的三乙胺，滴加完毕室温搅拌过夜。反应完成后，柱层析纯化，得16g中间体54-1。
Step 2：中间体54-2的制备
Figure PCTCN2022075322-appb-000042
将15g中间体54-1，90g盐酸(36％)，90g醋酸投入反应瓶中60℃搅拌40min反应结束，旋干溶剂得14g中间体54-2。
Step 3：中间体54-3的制备
Figure PCTCN2022075322-appb-000043
将5.0g中间体54-2，1.63g氯化亚砜，25g的1,2-二氯乙烷，2滴DMF投入反应瓶中90℃回流搅拌。一小时反应结束，旋干溶剂得5.1g中间体54-3。
实施例6：化合物54的制备
Figure PCTCN2022075322-appb-000044
将0.6g实施例5中描述的中间体54-3，0.120g乙二醇甲醚，10g二氯甲烷，0.2g三乙胺加入反应瓶中，氮气鼓吹，室温搅拌1h反应结束。反应完毕后，柱层析纯化，得0.350g化合物54。 1H NMR(400MHz,CDCl 3)δ7.97(dd,J＝7.7,2.0Hz,1H),7.40(d,J＝9.2Hz,1H),6.37(s,1H),5.36(q,J＝7.0Hz,1H),4.32(s,2H),3.60(t,J＝4.6Hz,2H),3.57(s,3H),3.36(s,3H),1.62(d,J＝7.1Hz,3H).LCMS(ESI)[M+H] +＝497.07,Found＝497.16.
实施例7：化合物61的制备
Step 1：化合物61的制备
Figure PCTCN2022075322-appb-000045
将290mg的丙烯基羟乙基醚，330mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例5中描述的中间体54-3(1.0g)的10mL的二氯甲烷溶液，滴毕后室温反应1h。反应完成后，柱层析纯化，得800mg化合物61。 1H NMR(400MHz,DMSO-d 6)δ8.14(d,J＝7.8Hz,1H),7.94(d,J＝9.6Hz,1H),6.62(d,J＝3.0Hz,1H),5.84(ddtd,J＝16.9,10.6,5.3,1.1Hz,1H),5.31(qt,J＝6.5,3.3Hz,1H),5.26–5.20(m,1H), 5.12(dq,J＝10.4,1.6Hz,1H),4.34–4.20(m,2H),3.95(dt,J＝5.3,1.5Hz,2H),3.60(ddd,J＝6.0,4.2,1.4Hz,2H),3.45–3.40(m,3H),1.53(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝523.08,Found＝522.96.
实施例8：化合物79的制备
Step 1：化合物79的制备
Figure PCTCN2022075322-appb-000046
将1g实施例5中描述的中间体54-3溶于1,2-二氯乙烷5mL，滴加丙炔醇乙氧基化合物(220mg)的1,2-二氯乙烷溶液，20℃搅拌10min后滴加三乙胺330mg。LCMS检测原料反应完全后，加入20mL盐酸(1N)洗涤，分液，无水硫酸钠干燥有机相，柱层析纯化得200mg无色油状液体为化合物79。 1H NMR(400MHz,Chloroform-d)δ7.97(dd,J＝7.7,2.1Hz,1H),7.40(d,J＝9.2Hz,1H),6.38(d,J＝1.0Hz,1H),5.36(q,J＝7.1Hz,1H),5.30(s,1H),4.17(dd,J＝2.4,0.7Hz,2H),3.76(dt,J＝6.9,3.0Hz,2H),3.59–3.55(m,3H),1.62(dd,J＝7.1,1.0Hz,3H),1.33–1.23(m,2H)..LCMS(ESI)[M+H] +＝521.07,Found＝521.21.
实施例9：化合物88的制备
Step 1：化合物88的制备
Figure PCTCN2022075322-appb-000047
将145.14mg的2-(甲基硫代)乙醇，199.21mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例5中描述的中间体54-3(0.60g)的3mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得545mg无色油状物为化合物88。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝7.8Hz,1H),7.94(d,J＝9.6Hz,1H),6.63(d,J＝2.9Hz,1H),5.32(dd,J＝7.0,2.0Hz,1H),4.39–4.21(m,2H),3.42(s,3H),2.83–2.66(m,2H),2.11–2.07(m,3H),1.55(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝512.04,Found＝512.54.
实施例10：化合物92的制备
Step 1：化合物92的制备
Figure PCTCN2022075322-appb-000048
将250.0mg的化合物88，10mL的二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，加入84.11mg间氯过氧苯甲酸，滴毕后室温反应2h。反应完成后，柱层析纯化，得177mg无色油状物为化合物92。 1H NMR(400MHz,DMSO-d 6)δ8.22(d,J＝7.7Hz,1H),8.01(d,J＝9.6Hz,1H),6.70(d,J＝2.9Hz,1H),5.45–5.35(m,1H),4.66–4.42(m,2H),3.49(s,3H),3.29–3.02(m,2H),2.73–2.62(m,3H),1.61(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝529.04,Found＝528.65.
实施例11：化合物93的制备
Step 1：化合物93的制备
Figure PCTCN2022075322-appb-000049
将97.77mg的2-甲砜基乙醇，99.61mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例5中描述的中间体54-3(0.30g)的2mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得192mg化合物93。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝7.7Hz,1H),7.94(d,J＝9.5Hz,1H),6.63(d,J＝3.2Hz,1H),5.44–5.28(m,1H),4.57–4.41(m,2H),3.55(t,J＝5.8Hz,2H),3.02(s,3H),1.54(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝545.03,Found＝544.58
实施例12：化合物96的制备
Figure PCTCN2022075322-appb-000050
在25mL单口瓶中加入0.5g实施例5中描述的中间体53-3，5mL的二氯甲烷，97.2mg的(S)-缩水甘油，0.17g三乙胺，室温搅拌过夜。反应完成后，加入5mL水搅拌、分液得有机相，无水硫酸钠干燥，减压蒸除溶剂。柱层析纯化，得215mg化合物96。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.7Hz,1H),7.40(d,J＝9.1Hz,1H),6.38(d,J＝1.1Hz,1H),5.37(q,J＝7.0Hz,1H),4.49(dd,J＝12.2,3.0Hz,1H),4.07–3.94(m,1H),3.57(s,3H),3.22(tt,J＝9.8,4.9Hz,1H),2.84(q,J＝4.4Hz,1H),2.63(dd,J＝4.7,2.6Hz,1H),1.62(t,J＝9.2Hz,3H).LCMS(ESI)[M+H] +＝495.05,Found＝495.05.
实施例13：化合物97的制备
Figure PCTCN2022075322-appb-000051
在25mL单口瓶中加入0.5g实施例5中描述的中间体53-3，5mL的二氯甲烷，97.2mg的(R)-缩水甘油，0.17g三乙胺，室温搅拌过夜。反应完成后，加入5mL水搅拌、分液得有机相，无水硫酸钠干燥，减压蒸除溶剂。柱层析纯化，得330mg化合物97。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.7Hz,1H),7.40(d,J＝9.2Hz,1H),6.37(d,J＝2.3Hz,1H),5.37(qd,J＝7.1,2.2Hz,1H),4.49(dd,J＝12.2,2.2Hz,1H),4.13–3.98(m,1H),3.57(d,J＝2.0Hz,3H),3.20(tt,J＝5.7,2.8Hz,1H),2.84(t,J＝4.5Hz,1H),2.67(dt,J＝10.9,5.6Hz,1H),1.63(d,J＝7.1Hz,3H).LCMS(ESI)[M+H] +＝495.05,Found＝495.30.
实施例14：中间体105-3的制备
Step 1：中间体105-1的制备
Figure PCTCN2022075322-appb-000052
将324.4mg的L-乳酸甲酯加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例1中描述的中间体1-8(1g)，后滴加394mg的三乙胺，滴毕后室温反应2h。反应完成后，柱层析纯化，得923mg中间体105-1。
Step 2：中间体105-2的制备
Figure PCTCN2022075322-appb-000053
将923mg中间体105-1，6.46g盐酸(36％)，6.46g醋酸加入反应瓶，回流40min，旋干反应液，得900mg中间体105-2。
Step 3：中间体105-3的制备
Figure PCTCN2022075322-appb-000054
将900mg中间体105-2、366.49mg二氯亚砜、2滴DMF、4.5g的1,2-二氯乙烷加入反应瓶，回流反应3h，旋干反应液，得800mg中间体105-3。
实施例15：化合物105的制备
Figure PCTCN2022075322-appb-000055
将0.6g实施例14中描述的中间体105-3，0.120g乙二醇单甲醚，10g二氯甲烷，0.2g三乙胺加入反应瓶中，氮气鼓吹，室温搅拌1h反应结束。反应完毕后，柱层析纯化，得0.40g化合物105。 1H NMR(400MHz,CDCl 3)δ7.97(dd,J＝7.7,2.0Hz,1H),7.40(d,J＝9.2Hz,1H),6.37(s,1H),5.36(q,J＝7.0Hz,1H),4.32(s,2H),3.60(t,J＝4.6Hz,2H),3.57(s,3H),3.36(s,3H),1.62(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝497.07,Found＝497.34.
实施例16：化合物112的制备
Figure PCTCN2022075322-appb-000056
将实施例14中描述的中间体105-3(1g)称于25ml单口瓶，加入二氯甲烷10mL，加入乙二醇单烯丙基醚268mg，加入三乙胺330mg，室温搅拌反应。15h后LCMS监测反应结束。加入5mL水搅拌，分液得到有机相。将有机相干燥，减压蒸除多余溶剂。柱层析纯化(PE:EA＝4:1)，得到768mg无色油状液体为化合物112。 1H NMR(400MHz,CDCl 3)δ7.97(dd,J＝7.7,1.9Hz,1H),7.40(d,J＝9.2Hz,1H),6.37(s,1H),5.87(ddd,J＝22.7,10.7,5.6Hz,1H),5.35(t,J＝7.0Hz,1H),5.27(dd,J＝17.2,1.5Hz,1H),5.18(d,J＝10.4Hz,1H),4.43–4.24(m,2H),4.00(d,J＝5.4Hz,2H),3.65(t,J＝4.8Hz,2H),3.57(s,3H),1.62(d,J＝7.1Hz,3H).LCMS(ESI)[M+H] +＝523.08,Found＝523.10
实施例17：化合物130的制备
Figure PCTCN2022075322-appb-000057
将1g实施例14中描述的中间体105-3、1,2-二氯乙烷5mL、丙炔醇乙氧基化合物(220mg)的1,2-二氯乙烷溶液，20℃搅拌10min后滴加入三乙胺330mg。LCMS检测原料反应完全后，加入20mL盐酸(1N)洗涤，分液，无水硫酸钠干燥有机相，柱层析纯化得无色油状液体230mg为化合物130. 1H NMR(400MHz,Chloroform-d)δ7.97(dd,J＝7.7,2.1Hz,1H),7.40(d,J＝9.2Hz,1H),6.38(d,J＝1.0Hz,1H),5.36(q,J＝7.1Hz,1H),5.30(s,1H),4.17(dd,J＝2.4,0.7Hz,2H),3.76(dt,J＝6.9,3.0Hz,2H),3.59–3.55(m,3H),1.62(dd,J＝7.1,1.0Hz,3H),1.33–1.23(m,2H)..LCMS(ESI)[M+H] +＝521.07,Found＝521.12.
实施例18：化合物139的制备
Step 1：化合物139的制备
Figure PCTCN2022075322-appb-000058
将145.14mg的2-(甲基硫代)乙醇，199.21mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例14中描述的中间体105-3(0.60g)的3mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得419mg无色油状物为化合物139。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝7.8Hz,1H),7.94(d,J＝9.6Hz,1H),6.63(d,J＝2.9Hz,1H),5.32(dd,J＝7.0,2.0Hz,1H),4.39–4.21(m,2H),3.42(s,3H),2.83–2.66(m,2H),2.11–2.07(m,3H),1.55(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝512.04,Found＝512.54.
实施例19：化合物143的制备
Step 1：化合物143的制备
Figure PCTCN2022075322-appb-000059
将250.0mg实施例18中描述的化合物139，10mL的二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，加84.11mg间氯过氧苯甲酸，滴毕后室温反应2h。反应完成后，柱层析纯化，得170mg无色油状物为化合物143。 1H NMR(400MHz,DMSO-d 6)δ8.21(d,J＝7.7Hz,1H),8.01(d,J＝9.6Hz,1H),6.70(d,J＝2.8Hz,1H),5.41(qt,J＝7.2,1.6Hz,1H),4.70–4.43(m,2H),3.48(s,3H),3.27–3.00(m,2H),2.65(d,J＝2.6Hz,3H),1.61(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝529.04,Found＝528.65.
实施例20：化合物144的制备
Step 1：化合物144的制备
Figure PCTCN2022075322-appb-000060
将97.77mg的2-甲砜基乙醇，99.61mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例14中描述的中间体105-3(0.30g)的2mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得166mg化合物144。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝7.7Hz,1H),7.94(d,J＝9.5Hz,1H),6.63(d,J＝3.2Hz,1H),5.43–5.32(m,1H),4.57–4.41(m,2H),3.55(t,J＝5.8Hz,2H),3.02(s,3H),1.54(d,J＝7.2Hz,3H).LCMS(ESI)[M+H] +＝545.03,Found＝544.58.
实施例21：化合物147的制备
Figure PCTCN2022075322-appb-000061
在25mL单口瓶中加入0.5g实施例14中描述的中间体105-3，5mL的二氯甲烷，97.2mg的(S)-缩水甘油，0.17g三乙胺，室温搅拌过夜。反应完成后，加入5mL水搅拌、分液得有机相，无水硫酸钠干燥，减压蒸除溶剂。柱层析纯化，得215mg化合物147。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.7Hz,1H),7.40(d,J＝9.1Hz,1H),6.38(d,J＝1.1Hz,1H),5.37(q,J＝7.0Hz,1H),4.49(dd,J＝12.2,3.0Hz,1H),4.07–3.94(m,1H),3.57(s,3H),3.22(tt,J＝9.8,4.9Hz,1H),2.84(q,J＝4.4Hz,1H),2.63(dd,J＝4.7,2.6Hz,1H),1.62(t,J＝9.2Hz,3H).LCMS(ESI)[M+H] +＝495.05,Found＝495.12.
实施例22：化合物148的制备
Figure PCTCN2022075322-appb-000062
在25mL单口瓶中加入0.5g实施例14中描述的中间体105-3，5mL的二氯甲烷，97.2mg的(R)-缩水甘油，0.17g三乙胺，室温搅拌过夜。反应完成后，加入5mL水搅拌、分液得有机相，无水硫酸钠干燥，减压蒸除溶剂。柱层析纯化，得240mg化合物148。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.7Hz,1H),7.40(d,J＝9.1Hz,1H),6.37(d,J＝2.2Hz,1H),5.37(dd,J＝7.1,2.1Hz,1H),4.49(dd,J＝12.2,2.3Hz,1H),4.07(ddd,J＝12.2,5.9,2.0Hz,1H),3.57(d,J＝1.9Hz,3H),3.20(tt,J＝5.8,2.8Hz,1H),2.83(t,J＝4.5Hz,1H),2.72–2.62(m,1H),1.63(d,J＝7.1Hz,3H).LCMS(ESI)[M+H] +＝495.05,Found＝495.06.
实施例23：中间体156-3的制备
Step 1：中间体156-1的制备
Figure PCTCN2022075322-appb-000063
将20.0g实施例1中描述的中间体1-8，4.86g的乳酸甲酯，100g的二氯甲烷加入反应瓶中，氮气鼓吹，室温搅拌。60min内滴加5.9g的三乙胺，滴加完毕室温搅拌过夜。反应完成后，柱层析纯化，得15.8g中间体156-1。
Step 2：中间体156-2的制备
Figure PCTCN2022075322-appb-000064
将15.0g中间体22-1，90g盐酸(36％)，90g醋酸投入反应瓶中60℃搅拌40min反应结束，旋干溶剂得13.7g中间体156-2。
Step 3：中间体156-3的制备
Figure PCTCN2022075322-appb-000065
将900mg中间体156-2、366.49mg二氯亚砜、2滴DMF、4.5g的1,2-二氯乙烷加入反应瓶，回流反应3h，旋干反应液，得820mg中间体156-3。
实施例24：化合物156的制备
Figure PCTCN2022075322-appb-000066
将0.6g实施例23中描述的中间体156-3，0.120g乙二醇单甲醚，10g二氯甲烷，0.2g的三乙胺加入反应瓶中，氮气鼓吹，室温搅拌1h反应结束。反应完毕后，柱层析纯化，得0.395g化合物156。 1H NMR(400MHz,CDCl 3)δ7.97(dd,J＝7.7,2.0Hz,1H),7.40(d,J＝9.2Hz,1H),6.37(s,1H),5.36(q,J＝7.0Hz,1H),4.32(s,2H),3.60(t,J＝4.6Hz,2H),3.57(s,3H),3.36(s,,3H),1.62(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝497.07,Found＝497.30.
实施例25：化合物163的制备
Figure PCTCN2022075322-appb-000067
参照实施例7、实施例16的方法，利用实施例23中描述的中间体156-3和2-(烯丙氧基)乙醇制备化合物163。
实施例26：化合物181的制备
Figure PCTCN2022075322-appb-000068
参照实施例8、实施例17的方法，利用实施例23中描述的中间体156-3和丙炔醇乙氧基化合物制备化合物181。 1H NMR(400MHz,Chloroform-d)δ7.97(dd,J＝7.7,2.1Hz,1H),7.40(d,J＝9.2Hz,1H),6.38(d,J＝1.0Hz,1H),5.36(q,J＝7.1Hz,1H),5.30(s,1H),4.17(dd,J＝2.4,0.7Hz,2H),3.76(dt,J＝6.9,3.0Hz,2H),3.59–3.55(m,3H),1.62(dd,J＝7.1,1.0Hz,3H),1.33–1.23(m,2H)..LCMS(ESI)[M+H] +＝521.07,Found＝521.11.
实施例27：化合物190的制备
Step 1：化合物190的制备
Figure PCTCN2022075322-appb-000069
将145.14mg的2-(甲基硫代)乙醇，199.21mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例23中描述的中间体156-3(0.60g)的3mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得409mg无色油状物为化合物190。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝7.8Hz,1H),7.94(d,J＝9.6Hz,1H),6.63(d,J＝2.9Hz,1H),5.32(dd,J＝7.0,2.0Hz,1H),4.39–4.21(m,2H),3.42(s,3H),2.83–2.66(m,2H),2.11–2.07(m,3H),1.55(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝512.04,Found＝512.54.
实施例28：化合物194的制备
Step 1：化合物194的制备
Figure PCTCN2022075322-appb-000070
将250.0mg的化合物190，10mL的二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，加84.11mg间氯过氧苯甲酸，滴毕后室温反应2h。反应完成后，柱层析纯化，得166mg无色油状物为化合物194。 1H NMR(400MHz,DMSO-d 6)δ8.21(d,J＝7.7Hz,1H),8.01(d,J＝9.6Hz,1H),6.70(d,J＝2.8Hz,1H),5.41(qt,J＝7.2,1.6Hz,1H),4.70–4.43(m,2H),3.48(s,3H),3.27–3.00(m,2H),2.65(d,J＝2.6Hz,3H),1.61(d,J＝7.0Hz,3H).LCMS(ESI)[M+H] +＝529.04,Found＝528.65.
实施例29：化合物195的制备
Step 1：化合物195的制备
Figure PCTCN2022075322-appb-000071
将97.77mg的2-甲砜基乙醇，99.61mg的三乙胺加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例23中描述的中间体156-3(0.30g)的2mL的二氯甲烷溶液，滴毕后室温反应2h。反应完成后，柱层析纯化，得168mg化合物195。 1H NMR(400MHz,DMSO-d 6)δ8.16(d,J＝7.7Hz,1H),7.94(d,J＝9.5Hz,1H),6.63(d,J＝3.2Hz,1H),5.43–5.32(m,1H),4.57–4.41(m,2H),3.55(t,J＝5.8Hz,2H),3.02(s,3H),1.54(d,J＝7.2Hz,3H).LCMS(ESI)[M+H] +＝545.03,Found＝544.58.
实施例30：化合物198的制备
Figure PCTCN2022075322-appb-000072
参照实施例12、实施例21的方法，利用实施例23中描述的中间体156-3和(S)-缩水甘油制备化合物198。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.7Hz,1H),7.40(d,J＝9.1Hz,1H),6.38(d,J＝1.1Hz,1H),5.37(q,J＝7.0Hz,1H),4.49(dd,J＝12.2,3.0Hz,1H),4.07–3.94(m,1H),3.57(s,3H),3.22(tt,J＝9.8,4.9Hz,1H),2.84(q,J＝4.4Hz,1H),2.63(dd,J＝4.7,2.6Hz,1H),1.62(t,J＝9.2Hz,3H).LCMS(ESI)[M+H] +＝495.05,Found＝495.04.
实施例31：化合物199的制备
Figure PCTCN2022075322-appb-000073
参照实施例13、实施例22的方法，利用实施例23中描述的中间体156-3和(R)-缩水甘油制备化合物199。 1H NMR(400MHz,CDCl 3)δ7.97(d,J＝7.7Hz,1H),7.40(d,J＝9.2Hz,1H),6.37(d,J＝2.3Hz,1H),5.37(qd,J＝7.1,2.2Hz,1H),4.49(dd,J＝12.2,2.2Hz,1H),4.13–3.98(m,1H),3.57(d,J＝2.0Hz,3H),3.20(tt,J＝5.7,2.8Hz,1H),2.84(t,J＝4.5Hz,1H),2.67(dt,J＝10.9,5.6Hz,1H),1.63(d,J＝7.1Hz,3H).LCMS(ESI)[M+H] +＝495.05,Found＝495.20.
实施例32：化合物207的制备
Step 1：中间体207-1的制备
Figure PCTCN2022075322-appb-000074
将2.36g的2-羟基异丁酸甲酯，1.91g的DMAP，50g的二氯甲烷加入反应瓶中，氮气鼓吹，室温搅拌。20min内滴加5g实施例1中描述的中间体1-8，滴加完毕，室温搅拌1h。反应完成后，柱层析纯化，得3.57g中间体207-1。
Step 2：中间体207-2的制备
Figure PCTCN2022075322-appb-000075
将3.57g中间体207-1，20g盐酸(36％)，20g醋酸投入反应瓶中120℃搅拌2h，反应结束，将反应液倒入100ml冰水中，EA萃取，有机相旋干，得2.78g中间体207-2。
Step 3：化合物207-3的制备
Figure PCTCN2022075322-appb-000076
将2.78g中间体207-2，1.1g氯化亚砜，30g的1,2-二氯乙烷，2滴DMF投入反应瓶中90℃回流搅拌。一小时反应结束，旋干溶剂得3.2g中间体207-3。
Step 4：化合物207的制备
Figure PCTCN2022075322-appb-000077
将0.3g中间体207-3，0.054g的乙二醇单甲醚，10g的二氯甲烷，0.089g三乙胺加入反应瓶中，氮气鼓吹，室温搅拌，反应结束后，加入5mL水搅拌，分液得到有机相。将有机相干燥，减压蒸除多余溶剂。柱层析纯化得到白色固体120mg为化合物207。 1H NMR(400MHz,CDCl 3)δ7.86(d,J＝7.7Hz,1H),7.38(d,J＝9.2Hz,1H),6.38(s,1H),4.50–4.18(m,2H),3.59(s,2H),3.57(s,3H),3.32(s,3H),1.69(s,6H).LCMS(ESI)[M +H] +＝511.08,Found＝511.12.
实施例33：化合物214的制备
Step 1：化合物214的制备
Figure PCTCN2022075322-appb-000078
将1.04g的丙烯基羟乙基醚，1.24g的DMAP，30g二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例32中描述的中间体207-3(3.2g)的20mL的二氯甲烷溶液，滴毕后室温反应1h。反应完成后，柱层析纯化，得600mg化合物214。 1H NMR(400MHz,DMSO-d 6)δ8.07(d,J＝7.8Hz,1H),7.92(d,J＝9.6Hz,1H),6.63(s,1H),5.90–5.73(m,1H),5.25–5.08(m,2H),4.27–4.19(m,2H),3.91(dt,J＝5.3,1.6Hz,2H),3.59–3.55(m,2H),3.42(d,J＝1.3Hz,3H),1.63(s,6H).LCMS(ESI)[M+H] +＝537.10,Found＝536.98.
实施例34：化合物249的制备
Figure PCTCN2022075322-appb-000079
将0.71g的(S)-缩水甘油，0.5g的DMAP,2g三乙胺和2mL的二氯甲烷加入反应瓶，冰浴降温、氮气鼓吹，滴加2.57g实施例32中描述的中间体207-3溶于二氯甲烷溶液20mL，滴毕室温反应3h，反应完成后，柱层析纯化，得3g油状化合物为化合物249。 1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝7.6Hz,1H),7.39(d,J＝9.1Hz,1H),6.38(s,1H),4.45(dd,J＝12.2,3.4Hz,1H),4.04(dd,J＝12.2,6.0Hz,1H),3.57(s,3H),3.21(dq,J＝6.4,3.3Hz,1H),2.83(t,J＝4.5Hz,1H),2.64(dd,J＝4.9,2.6Hz,1H),1.70(s,6H).LCMS(ESI)[M+H] +＝509.07,Found＝508.93.
实施例35：化合物250的制备
Figure PCTCN2022075322-appb-000080
将0.71g的(R)-缩水甘油，0.5g的DMAP,2g三乙胺和2mL的二氯甲烷加入反应瓶，冰浴降温、氮气鼓吹，滴加2.57g实施例32中描述的中间体207-3的二氯甲烷溶液20mL，滴毕室温反应3h，反应完成后，柱层析纯化，得2.9g油状化合物为化合250。 1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝7.7Hz,1H),7.39(d,J＝9.2Hz,1H),6.38(s,1H),4.44(dd,J＝12.2,3.4Hz,1H),4.04(dd,J＝12.2,6.0Hz,1H),3.56(s,3H),3.20(dq,J＝6.1,3.5Hz,1H),2.82(t,J＝4.5Hz,1H),2.63(dd,J＝4.8,2.6Hz,1H),1.70(s,6H).LCMS(ESI)[M+H] +＝509.07,Found＝509.10.
实施例36：化合物251的制备
Step 1：化合物251的制备
Figure PCTCN2022075322-appb-000081
参照实施例34、实施例35的方法，利用实施例32中描述的中间体207-3和(±)-环氧丙醇制备化合物251。 1H NMR(400MHz,Chloroform-d)δ7.87(d,J＝7.6Hz,1H),7.39(d,J＝9.1Hz,1H),6.38(s,1H),4.45(dd,J＝12.2,3.4Hz,1H),4.04(dd,J＝12.2,6.0Hz,1H),3.57(s,3H),3.21(dq,J＝6.4,3.3Hz,1H),2.83(t,J＝4.5Hz,1H),2.64(dd,J＝4.9,2.6Hz,1H),1.70(s,6H).LCMS(ESI)[M+H] +＝509.07,Found＝508.97.
实施例37：化合物258的制备
Step 1：化合物258-1的制备
Figure PCTCN2022075322-appb-000082
将0.6g的1-羟基-1-环丙羧酸甲酯，0.57g的DMAP，25g二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例1中描述的中间体1-8(1.22g)的10mL的二氯甲烷溶液，滴毕后室温反应1h。反应完成后，柱层析纯化，得1.1g中间体258-1。
Step 2：化合物258-2的制备
Figure PCTCN2022075322-appb-000083
将1.1g中间体258-1，8g盐酸(36％)，8g醋酸投入反应瓶中110℃搅拌4h，反应结束，将反应液倒入100ml冰水中，EA萃取，有机相旋干，得1.06g中间体258-2。
Step 3：化合物258-3的制备
Figure PCTCN2022075322-appb-000084
将1.06g中间体258-2，0.42g氯化亚砜，20g的1,2-二氯乙烷，2滴DMF投入反应瓶中90℃回流搅拌。一小时反应结束，旋干溶剂得1.1g中间体258-3。
Step 4：化合物258的制备
Figure PCTCN2022075322-appb-000085
将0.211g的乙二醇单甲醚，0.323g的三乙胺，15g二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加中间体258-3(1.0g)的10mL的二氯甲烷溶液，滴毕后室温反应1h。反应完成后，柱层析纯化，得201mg化合物258。 1H NMR(400MHz,DMSO-d 6)δ8.21(d,J＝7.6Hz,1H),8.01(d,J＝9.4Hz,1H),6.70(s,1H),4.29(t,J＝4.7Hz,2H),3.57(t,J＝4.6Hz,2H),3.49(s,3H),3.29(s,3H),1.67– -1.48(m,4H).LCMS(ESI)[M+H] +＝509.07,Found＝508.92.
实施例38：化合物300的制备
Step 1：化合物300的制备
Figure PCTCN2022075322-appb-000086
将0.308g的(S)-缩水甘油，0.485g的三乙胺，20g二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例37中描述的中间体258-3(1.5g)的15mL的二氯甲烷溶液，滴毕后室温反应1h。反应完成后，柱层析纯化，得212mg化合物300。 1H NMR(400MHz,DMSO-d 6)δ8.22(d,J＝7.8Hz,1H),8.01(d,J＝9.6Hz,1H),6.69(s,1H),4.52(dd,J＝12.3,2.6Hz,1H),4.03(dd,J＝12.3,6.3Hz,1H),3.51–3.45(m,3H),3.24(ddt,J＝6.7,4.2,2.6Hz,1H),2.83(dd,J＝5.0,4.2Hz,1H),2.68(dd,J＝5.0,2.6Hz,1H),1.68–1.51(m,4H).LCMS(ESI)[M+H] +＝507.05,Found＝506.96.
实施例39：化合物301的制备
Step 1：化合物301的制备
Figure PCTCN2022075322-appb-000087
将0.205g的(R)-缩水甘油，0.323g的三乙胺，15g二氯甲烷加入反应瓶，冰浴降温搅拌，氮气鼓吹，滴加实施例37中描述的中间体258-3(1.0g)的15mL的二氯甲烷溶液，滴毕后室温反应1h。反应完成后，柱层析纯化，得222mg化合物301。 1H NMR(400MHz,DMSO-d 6)δ8.15(d,J＝7.8Hz,1H),7.94(d,J＝9.6Hz,1H),6.63(s,1H),4.46(dd,J＝12.3,2.7Hz,1H),3.97(dd,J＝12.3,6.2Hz,1H),3.46–3.40(m,3H),3.18(ddt,J＝6.7,4.2,2.6Hz,1H),2.77(dd,J＝5.0,4.3Hz,1H),2.62(dd,J＝5.0,2.6Hz,1H),1.61–1.45(m,4H).LCMS(ESI)[M+H] +＝507.05,Found＝507.10.
实施例40：化合物302的制备
Step 1：化合物302的制备
Figure PCTCN2022075322-appb-000088
参照实施例38、实施例39的方法，利用实施例37中描述的中间体258-3和(±)-环氧丙醇制备化合物302。 1H NMR(400MHz,DMSO-d 6)δ8.22(d,J＝7.8Hz,1H),8.01(d,J＝9.6Hz,1H),6.69(s,1H),4.52(dd,J＝12.3,2.6Hz,1H),4.03(dd,J＝12.3,6.3Hz,1H),3.51–3.45(m,3H),3.24(ddt,J＝6.7,4.2,2.6Hz,1H),2.83(dd,J＝5.0,4.2Hz,1H),2.68(dd,J＝5.0,2.6Hz,1H),1.68–1.51(m,4H).LCMS(ESI)[M+H] +＝507.05,Found＝506.88.
实施例41：室内除草活性测定
本发明化合物的除草活性测试方法如下：
苗前：将定量的禾本科杂草(稗草、牛筋草、马唐、日本看麦娘、菵草、千金子、棒头草、看麦娘、多花黑麦草、早熟禾)、阔叶杂草(鳢肠、反枝苋、野油菜、牛繁缕、小飞蓬、田菁)和碎米莎草种子分别播于直径7cm的地步带孔的装有营养土(沙质土壤，pH6.1,有机物1％)的塑料盆钵中，播种后适量覆土，然后采用底部吸水的方式浸湿土壤，置于恒温光照培养室内培养24h后进行土壤喷雾，喷雾采用农业部南京农业机械化研究所生产的3WP-2000型行走式喷雾塔，主轴转速96mm/r，喷雾高度300mm，喷头有效喷幅350mm,喷雾面积0.35m 2,喷头流量390mL/min；
苗后：将适量的禾本科杂草(稗草、牛筋草、马唐、日本看麦娘、菵草、千金子、棒头草、看麦娘、多花黑麦草、早熟禾)、阔叶杂草(鳢肠、反枝苋、野油菜、牛繁缕、小飞蓬、田菁)和碎米莎草种子分别播于直径分别播于直径7cm的地步带孔的装有营养土(沙质土壤，pH 6.1,有机物1％)的塑料盆钵中，播种后适量覆土，然后采用底部吸水的方式浸湿土壤，置于恒温光照培养室内培养至2～4叶期进行茎叶喷雾处理。试材处理后置于实验室内待药液自然阴干后置于恒温光照培养室内培养，21天后测定结果。
防除效果分级标准：
A表示抑制率为大于等于85％至100％；
B表示抑制率为大于等于70％至小于85％；
C表示抑制率为大于等于55％至小于70％；
D表示抑制率小于55％。
试验结果表明，通式(I)化合物在30g a.i./hm 2剂量下对多种杂草普遍具有优异的防治效果，达到A级的防效。
按照上述测试方法，选取部分通式(I)化合物与专利US5183492A中具体公开的化合物Butafenacil(专利说明书中化合物47)及专利US5183492A具体公开化合物CK(专利说明书中的化合物1)的进行除草活性的平行试验，施用剂量为7.5g a.i./ha和15g a.i./ha。结果见表2：
表2：部分通式Ⅰ化合物及对照化合物的除草活性(苗后，鲜重抑制率％)
Figure PCTCN2022075322-appb-000089
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变化和改进，这些都属于本发明的保护范围。

Claims (10)

  1. 一种含羧酸酯片段的尿嘧啶类化合物，其结构如通式(I)所示：
    Figure PCTCN2022075322-appb-100001
    式中：
    R 1、R 2分别选自氢或甲基；或者R 1和R 2与所连接的碳一起形成三元环；
    R 3选自C 1～3烷氧C 1～3烷基、C 1～3卤代烷氧C 1～3烷基、C 2～6烯氧C 1～3烷基、C 2～6卤代烯氧C 1～3烷基、C 2～6炔氧C 1～3烷基、C 2～6卤代炔氧C 1～3烷基、C 1～3烷S(O) nC 1～3烷基、C 3～6环氧烷基C 1～3烷基或C 3～9环氧烷基；
    n＝0，1或2；
    当R 1选自氢、R 2选自甲基时，与其相连的碳原子可选自R型或S型，或者为二者的混合物；混合物中，R与S的比例为1：99至99：1。
  2. 如权利要求1所述的含羧酸酯片段的尿嘧啶类化合物，其特征在于：
    R 1、R 2分别选自氢或甲基；或者R 1和R 2与所连接的碳一起形成三元环；
    R 3选自C 1～3烷氧C 1～3烷基、C 1～3卤代烷氧C 1～3烷基、C 2～6烯氧C 1～3烷基、C 2～6卤代烯氧C 1～3烷基、C 2～6炔氧C 1～3烷基、C 2～6卤代炔氧C 1～3烷基、C 3～6环氧烷基C 1～3烷基或C 3～9环氧烷基；
    当R 1选自氢、R 2选自甲基时，与其相连的碳原子可选自R型或S型，或者为二者的混合物；混合物中，R与S的比例为1：99至99：1。
  3. 如权利要求1所述的含羧酸酯片段的尿嘧啶类化合物，其特征在于：
    R 1、R 2分别选自氢或甲基；
    R 3选自C 1～3烷氧-C 1～3烷基、C 1～3卤代烷氧-C 1～3烷基、C 2～6烯氧-C 1～3烷基、C 2～6卤代烯氧-C 1～3烷基、C 2～6炔氧-C 1～3烷基、C 2～6卤代炔氧-C 1～3烷基、C 3～6环氧烷基-C 1～3烷基或C 3～9环氧烷基；
    当R 1选自氢、R 2选自甲基时，与其相连的碳原子可选自R型或S型，或者为二者的混合物，混合物中，R与S的比例为1：99至99：1。
  4. 一种制备权利要求1-3中任意一项所述的含羧酸酯片段的尿嘧啶类化合物的方法，其特征在于，该方法包括：在溶剂存在的条件下，将式(II)所示的酸类化合物与不同的取代的醇、卤代或磺酸酯化合物进行接触反应，
    Figure PCTCN2022075322-appb-100002
    其中，在通式(I)和(II)，所涉及的R 1、R 2和R 3的定义均与权利要求1中的定义相同。
  5. 如权利要求4所述的方法，其特征在于，所述反应温度为0～160℃。
  6. 如权利要求4所述的方法，其特征在于，所述反应时间为2～15h。
  7. 如权利要求4所述的方法，其特征在于，所述反应溶剂选自二氯甲烷、1,2-二氯乙烷、四氢呋喃、乙腈、1,4-二氧六环、甲苯、邻二甲苯、间二甲苯、对二甲苯、正庚烷、正辛烷和正壬烷中的至少一种。
  8. 如权利要求4所述的方法，其特征在于，所述式(II)所示的羧酸类化合物与不同的取代的醇、卤代或磺酸酯化合物用量摩尔比为1：1～4。
  9. 如权利要求1～3所述的含羧酸酯片段的尿嘧啶类化合物用于防治杂草的用途。
  10. 一种组合物，其特征在于以权利要求1～3所述的含羧酸酯片段的尿嘧啶类化合物为活性成分，组合物中活性组分的重量百分含量为0.1～99.9％。
PCT/CN2022/075322 2021-02-07 2022-02-05 一种含羧酸酯片段的尿嘧啶类化合物、其制备方法、除草组合物和用途 WO2022166938A1 (zh)

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WO2023017518A1 (en) * 2021-08-09 2023-02-16 Adama Agan Ltd. A new process of saflufenacil production using novel intermediates
WO2024027767A1 (zh) * 2022-08-04 2024-02-08 江苏中旗科技股份有限公司 包含羧酸酯片段的尿嘧啶类化合物的除草组合物及其应用

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CN117551044A (zh) * 2022-08-04 2024-02-13 江苏中旗科技股份有限公司 一种制备含羧酸酯片段的尿嘧啶类化合物的方法

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WO2024027767A1 (zh) * 2022-08-04 2024-02-08 江苏中旗科技股份有限公司 包含羧酸酯片段的尿嘧啶类化合物的除草组合物及其应用

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